Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons
Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons
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DOI：
10.1016/j.nbd.2011.12.033
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发表时间：
2012-03-01
影响因子：
6.1
通讯作者：
Kwak, Shin
中科院分区：
文献类型：
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作者：
Hideyama, Takuto;Yamashita, Takenari;Kwak, Shin
肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是最常见的成人发病的致死性运动神经元疾病。在散发性ALS患者的脊髓运动神经元中，GluA 2（L-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的亚基）的正常RNA编辑效率低下。作用于RNA 2的腺苷脱氨酶（ADAR 2）特异性介导GluA 2的谷氨酰胺/精氨酸（Q/R）位点处的RNA编辑，并且表达Q/R位点未编辑的GluA 2的运动神经元在条件性ADAR 2敲除小鼠中经历缓慢死亡。因此，研究ADAR 2介导的GluA 2 Q/R位点编辑是否普遍存在于ALS患者的运动神经元中，将为ALS的发病机制提供深入了解。我们分析了29名ALS患者与正常和疾病对照受试者相比，单个激光捕获运动神经元中GluA 2 Q/R位点编辑的程度。此外，我们分析了阿达尔家族的三个成员（ADAR 1、ADAR 2和ADAR 3）在表达未编辑的GluA 2 mRNA和仅表达编辑的GluA 2 mRNA的ALS运动神经元中的酶活性。Q/R位点未编辑的-GluA 2 mRNA在所有ALS病例的运动神经元中表达的比例很大。相反，正常和疾病对照受试者的运动神经元仅表达编辑的GluA 2 mRNA。在ALS患者的所有运动神经元中，ADAR 2（而非ADAR 1或ADAR 3）均显著下调，在表达Q/R位点未编辑的GluA 2 mRNA的运动神经元中的下调程度比仅表达Q/R位点编辑的GluA 2 mRNA的运动神经元更大。这些结果表明，ADAR 2下调是与ALS中运动神经元死亡相关的深刻病理变化。(C)2011 Elsevier Inc. All rights reserved.
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset fatal motor neuron disease. In spinal motor neurons of patients with sporadic ALS, normal RNA editing of GluA2, a subunit of the L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, is inefficient. Adenosine deaminase acting on RNA 2 (ADAR2) specifically mediates RNA editing at the glutamine/arginine (Q/R) site of GluA2 and motor neurons expressing Q/R site-unedited GluA2 undergo slow death in conditional ADAR2 knockout mice. Therefore, investigation into whether inefficient ADAR2-mediated GluA2 Q/R site-editing occurs universally in motor neurons of patients with ALS would provide insight into the pathogenesis of ALS. We analyzed the extents of GluA2 Q/R site-editing in an individual laser-captured motor neuron of 29 ALS patients compared with those of normal and disease control subjects. In addition, we analyzed the enzymatic activity of three members of the ADAR family (ADAR1, ADAR2 and ADAR3) in ALS motor neurons expressing unedited GluA2 mRNA and those expressing only edited GluA2 mRNA. Q/R site-unedited-GluA2 mRNA was expressed in a significant proportion of motor neurons from all of the ALS cases examined. Conversely, motor neurons of the normal and disease control subjects expressed only edited GluA2 mRNA. ADAR2, but not ADAR1 or ADAR3, was significantly downregulated in all the motor neurons of ALS patients, more extensively in those expressing Q/R site-unedited GluA2 mRNA than those expressing only Q/R site-edited GluA2 mRNA. These results indicate that ADAR2 downregulation is a profound pathological change relevant to death of motor neurons in ALS. (C) 2011 Elsevier Inc. All rights reserved.